1. Medical Theraphy of Idiopathic OAT Hyun-Joo Kim M.D. Department of Urology Pochon CHA University

2. Medical Theraphy of Idiopathic OAT  Current Treatment Modalities  Considerations  Mission

3. OAT as a Diagnosis? Concept of OAT ≒ FEVER OAT is a Phenomenon !

4. Criteria of OAT on Semen Analysis Oligospermia<20x10 6 /ml (WHO) severe<5x10 6 /ml crypto<1x10 6 /ml a fewmotile or immotile Astheno<50% (WHO) severe<10% Terato<30% (WHO) <14% (Strict Criteria) severe< 4%(Strict Criteria)

5. Idiopathic v.s Specific  Specific Causes Secondary Hypogonadism Varicocele Retrograde Ejaculation Infections Immunologic Infertility  Idiopathic Causes All unknown causes

6. Prevalence of Male Infertility Normal/OAT84.3% Azoospermia15.7% a Obstructive 6.3% b Non-obstructive 9.4% c a. 981/6242 semen analysis (95.9-97) b. 165/416 testis bx (95.9-97) c. 251/416 testis bx (95.9-97) from CHA

7. Prevalence of Abnormal Semen Parameters  All parameter43%  Motility39%  Oligospermia10%  Morphology 8% from Greenberg, 1987

8. Specific Causes v.s Idiopathic  Varicocele39%  Obstructive 8%  Mechanical 8%  Endocrine 6%  Developmental 5%  Immunologic 1%  Idiopathic33% from Schlegel and Pavlovich, 1997

9. Current Management Modality of Idiopathic OAT  Pharmacological  Sperm processing  ART

10. Management Idiopathic OAT: Pharmacological Treatment  Hormonal Treatment GnRH HCG/HMG Purified or recombinant FSH Androgens Anti-Estrogens  Non-Hormonal Treatment Kallikrein Bromocriptine Anti-Oxidant: Vit. C or E

11. Spermatogenesis I

12. Meta-Analysis of Medical Treatment in OAT Antiestrogens n=459 FSH n=223 Androgens n=1025 Kinin enhancing agents n=197 odds ratio 0.250.5 125

13. Role of FSH ( in Monkey) Normal Normal + FSH Hypophysectomy + T Hypophysectomy + T + FSH

14. FSH on Spermatogenesis I  Quantitative Influence Increase A-pale spermatogonia Spermatocyte, Spermatid  Qualititative Influence Restore defective spermatozoal maturation (esp. acrosomal cap)  For adequate concentration of intratubular Testosterone LH for T, FSH for ABP

15. FSH on Spermatogenesis II  Stimulate Sertoli cell to enhance FSH dependent functions  Support spermatogenesis without interfering negatively with Leydig cell physiology and without locally increasing Estrogen level  Modulate intra-testicular paracrine and autocrine mechanism

16. Variable Results of FSH Treatment  Dose: may not high enough  Frequency : short half-life  Duration : too short  Reduction in FSH receptor activity  Low proliferative activity of A-pale spermatogonia  Elevated endogenous level of FSH

17. Management Plan for Idiopathic OAT I  Considerations: Female factor, Severity of OAT, Previous Treatment, P/E  Oligo: T.Vol.(normal), FF(-): Empirical Tx > 3mos. T.Vol.<10cc or FF(+): ART Severe OAT: ART A few motile/immotile: ICSI p.r.n) oocyte freezing  Astheno: >10%, FF(-): Empirical Tx > 3mos. or IUI 3mos. or ICSI p.r.n) T-Bx 0%: Vital >20-30% : ICSI Vital <10% : TESE-culture

18. Management Plan for Idiopathic OAT II  Terato: General condition control Empirical Tx > 3mos. + IUI  Severe Terato: General condition control Empirical Tx > 3mos. p.r.n) IUI or ICSI FF(+): ICSI

19. Treatment of Male Infertility?  Relative Concept of FERTILITY  Consider Cumulative P.R  Natural Pregnancy or ART?

20. Cumulative Live Birth Rate 52.5%/36mos. 25.2%/36mos. From Kamischke, 1999

21. Male Fecundity from Schrader, 1988 Intra-and inter-individual variation of semen parameters in human, coefficient of variation Semen parameters COA of Individual Intra – individual Inter- Individual Concentration4479 Normal forms1419 Motile sperm4526 Linear progression 1619

22. Drugs, Chemical, and Metabolites possible to exert toxic actions on the male gonad Parent compoundUsageMetabolites Amiodaroneanti-arrhythmiaDesethylamiodarone Cephalosporin analoguesanti-microbial drugN-Methyltetrazolethiol Valproic acidanti-epileptic drugIsomers of 2-ethyl hexanol(?) Diethylhexyl phthalateplasticizerMono-ethylhexylphthalate (MEHP) (DEHP)2-ethyl hexanol(?) DibromochloropropanefungicideDichloropropene derivatives (?) (DBCP) Ethylene glycolindustrial solvent2-Methoxyacetaldehyde (MALD) monoethyl ether n-Hexaneenvironmental toxicant2,5-Hexanedione Acrylamideindustrial useN-Methylacrylamide, N-isopropylacrylamide VinclozolinfungicideButenoic acid derivatives enanilide metabolite 1. Only substituent is a testicular toxin, not cephalosporin 2. Questionable testicular toxin but probably teratogenic from Thomas, 1996

23. Environmental/Lifestyle factors to affect male fertility  Cigarette smoke  Ingestion of female sex hormones  Exposure to heavy metals(i.e. lead, arsenic)  Alcohol  Marijuana, anabolic steroids, cocaine  Cancer chemotherapeutics  Radiation exposure  Increased testicular temperature  Stress  Lack of exercise  Caffeine

24. Medical Treatment of OAT : Anti-Estrogens

25. Medical Treatment of OAT : FSH

26. Causes of Male Infertility  Pre-Testicular Disorders of H-P-G axis  Testicular Spermatogenic Defects  Post-Testicular Epididymal Dysfunction Obstructive change of passage Infection of Accessary glands

27. Prevalence of Male Infertility  Pre-Testicular 8%  Testicular80% (Idiopathic > 25%)  Post-Testicular12% from Sigman, 1987

28. Spermatogenesis I

29. Testicular Causes: Spermatogenic Defects  Germ cell Defects  Somatic cell Defects  Communications Defects

30. Testicular expression of cytokines CytokinesProductionReceptor Leydig cellSertoli cellGerm cells IL-1L, S,G+++ IL-6L, S,++? TNFa G?+? IFN P,S,Gnnn c-kit ligand S+n+ EGF/TGFaL,P,S,G+++ TGFb P,S+++ ActivinL,P,S+++ InhibinL, S+++ IGF-IL,P,S,G+++ FGFL,P,S,G+++ NGF Gn+- PDGFL, S++-

31. Function of Testis  Dependent on Gonadotropins and Correct action of local growth factors  Major system Endocrine System  Local factors depend on Endocrine system “act as an adjusted fine local relay for the endocrine system”

32. Spermatogenic Defects OAT from  Inadequate Gonadotropin activity  Imbalance in the intratesticular paracrine regulation  Mystery

33. Possible Diagnostic Tools of Spermatogenic Defects  Sperm chromosomal study  Gonadotropin assay  Germ cell and Somatic cell activity study  Receptors study

34. Medical Treatment of idiopathic OAT For the good results of treatment, Pt. SELECTION by Correct Diagnosis is mandatory !